Epstein Barr virus (EBV) is the cause of infectious mononucleosis and is associated with a number of cancers including Burkitt lymphomas and lymphomas in transplant recipients. We have been studying EBV DNA in the blood of transplant recipients or other immunocompromised persons, patients with chronic active EBV disease, and patients with diseases in which EBV may be a cofactor. The treatment of EBV-associated cancers often requires chemotherapy which is often very toxic and is not always successful. New forms of therapy are needed for treatment of these diseases. Tubacin is a small molecule that inhibits histone deacetylase 6, a protein that is important for assembly of microtubules and for motility in the cell. Tubacin also blocks aggresome activity. Aggresomes are structures in the cell that sequester misfolded or infolded proteins that would otherwise be toxic to the cell. In 2009 we tested the effect of tubacin on EBV-positive Burkitt lymphoma cells and on normal human B lymphocytes that had been immortalized by EBV infection (EBV-transformed B lymphocytes). We found that EBV-positive Burkitt lymphoma cells were killed by lower doses of tubacin than EBV-transformed B lymphocytes. Tubacin induced programmed cell death (apoptosis) of EBV-transformed B lymphocytes, but did not induce apoptosis of EBV-positive Burkitt lymphoma cells. Instead, tubacin killed EBV-positive Burkitt lymphoma cells by inducing reactive oxygen species which cause cell damage and death. Previously, we showed that bortezomib, which inhibits the activity of proteasomes that degrade proteins in the cell, induces programmed cell death of EBV-transformed B lymphocytes and kills EBV-positive Burkitt lymphoma cells. In 2009 we found that the combination of bortezomib and tubacin acts in synergy to kill EBV-positive Burkitt lymphoma cells and EBV-transformed B lymphocytes. These findings suggest that the combination of a proteasome inhibitor, such as bortezomib, and an HDAC6 inhibitor, such as tubacin, may represent a useful strategy for the treatment of certain EBV-associated B cell lymphomas. EBV causes disease in humans and does not infect small animals. To help to identify the mechanisms of immune protection against EBV and to evaluate promising vaccine candidates, we developed a small animal model to study EBV pathogenesis. In 2009, we collaborated with investigators at the Rockefeller University and showed that transplanted irradiated immunocompromised mice with human CD34+ progenitor cells could be infected with EBV and that the transplanted human cells could induce an immune response to the virus. We showed that primary T lymphocyte responses in the mice with reconstituted human immune system components control infection with EBV. These T lymphocytes produced interferon-gamma and were restricted for responding to cells with specific cell surface proteins (human leukocyte antigens) and for cells expressing EBV proteins. The immune response in these EBV-infected mice was similar to that seen in EBV-infected mice in that the T lymphocyte response against EBV proteins expressed during virus growth was greater than the T lymphocyte response against EBV proteins expressed when the virus is latent. Transplant patients who have reduced T cell function often have high levels of EBV in the blood and are at risk of developing EBV lymphomas. We found that depletion of T cells in the mice also resulted in elevation of EBV DNA in the blood and led to EBV-associated lymphomas in the animals. Depletion of both CD4+ T lymphocytes and CD8+ T lymphocytes abolished immune control of EBV. Therefore, this mouse model recapitulates many of the features of EBV infection in humans, including T lymphocyte-mediated immune control of EBV that can prevent virus-associated cancers.